(Circulation. 2001;103:2323.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Fibrin D-Dimer and Coronary Heart Disease
Prospective Study and Meta-Analysis
From the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Medicine, University of Oxford, Oxford (J.D.); Department of Public Health Sciences, St George’s Hospital Medical School, London (P.W.); Department of Primary Care and Population Sciences, Royal Free and University College of London Medical School (M.W., L.L., A.T.); ICRF Cancer Epidemiology Unit, Radcliffe Infirmary, Oxford (P.A.); and the University Department of Medicine, Glasgow Royal Infirmary, Glasgow (A.R., G.D.O.L.), UK.
Correspondence to Dr Danesh, Clinical Trial Service Unit, University of Oxford, Radcliffe Infirmary, Harkness Building, Oxford OX2 6HE, England.
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionsReferences |
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Background—It is unknown whether modest increases of fibrin D-dimer, a circulating marker of fibrin turnover, are relevant to coronary heart disease (CHD) in the general population.
Methods and Results—We measured serum concentrations of D-dimer antigen in the stored baseline blood samples of 630 CHD cases and 1269 controls "nested" in a prospective cohort of 5661 men who were monitored for 16 years, and we conducted a meta-analysis of previous relevant studies to place our findings in context. In a comparison of men in the top third compared with those in the bottom third of baseline fibrin D-dimer values (tertile cutoffs, >94 versus <49 ng/mL), the odds ratio for CHD was 1.67 (95% CI, 1.31 to 2.13; P<0.0001) after adjustments for age and town. The odds ratio increased slightly after further adjustment for smoking, other classic risk factors, and indicators of socioeconomic status (1.79; 95% CI, 1.36 to 2.36). Strong correlations were observed of fibrin D-dimer values with circulating concentrations of C-reactive protein and serum amyloid A protein but not with smoking, blood lipids, blood pressure, and other risk factors.
Conclusion—Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.
Key Words: heart diseases • epidemiology • coagulation • fibrinolysis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Circulating concentrations of fibrin D-dimer reflect the extent of fibrin turnover in the circulation, as this antigen is present in several degradation products from the cleavage of cross-linked fibrin by plasmin.1 2 Highly elevated D-dimer values occur in various disorders in which the coagulation system is excessively activated, such as acute venous thromboembolism.3 It has been suggested that modestly elevated circulating D-dimer values reflect minor increases in blood coagulation, thrombin formation, and turnover of cross-linked intravascular fibrin (which is partly intra-arterial in origin) and that these increases may be relevant to coronary heart disease (CHD).2 We report the largest and most prolonged study thus far relating baseline values of D-dimer to subsequent CHD, and we report a meta-analysis of previous relevant studies to place our findings in context.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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From 1978 to 1980, 7735 men aged 40 to 59 years (response rate, 78%) were randomly selected from general practice registers in each of 24 British towns and entered into the British Regional Heart Study.4 Nurses administered questionnaires, made physical measurements, recorded an ECG, and, in 5661 men in 18 of the towns, collected nonfasting venous blood samples, from which serum was stored at -20°C for subsequent analysis.4 All men have been monitored subsequently for all-cause mortality and for cardiovascular morbidity, with a follow up loss of <1% to date.5 The present 643 cases included 279 CHD deaths and 364 cases of nonfatal myocardial infarction occurring between 1978 and 1996 (comprising cases reported in 2 previous studies).6 7 Fatal cases were ascertained through National Health Service Central Registers (death certificates with ICD-9 codes 410 to 414); the diagnosis of nonfatal myocardial infarction was based on reports from general practitioners, supplemented by regular reviews of general practice records, and diagnosis was in accordance with World Health Organization criteria.8 A total of 1278 controls "frequency matched" to cases on town of residence and age in 5-year bands were randomly selected from among men who had survived to the end of the study period free from incident CHD. D-dimer measurements were available for 630 of these cases and 1269 of these controls.
Laboratory workers who were blinded to case-control
status measured serum concentrations of D-dimer using a sensitive
enzyme immunoassay,9 with a
correlation coefficient of 0.93 for values in paired plasma and serum
samples from 20 healthy individuals. Because of fluctuations of
D-dimer values over time, case-control comparisons of measured baseline
values tend to underestimate any associations with CHD
risk.10 D-dimer measurements
were made in pairs of samples collected at an interval of 5 years in
1009 controls in a separate
study,11 yielding a
self-correlation coefficient of 0.51 (G.D.O. Lowe et al, unpublished
data); these data were used to estimate the magnitude of regression
dilution and to correct for
it.12 We prespecified
case-control analyses by thirds of D-dimer values in controls,
involving unmatched stratified logistic regression fitted by
unconditional maximum likelihood (STATA Corporation). For associations
between D-dimer and a variety of known and suspected risk factors,
emphasis was mainly given to differences more extreme than 2.6 SD
(2-tailed P
0.01) to
make some allowance for multiple comparisons. A meta-analysis
was conducted of prospective studies of D-dimer and CHD with >1 year
of follow-up published before 2000 using methods described
previously.12 Cases were
compared only with controls within the same studies to avoid potential
biases.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Present Prospective Study
There were highly significant differences between cases and controls with respect to various known vascular risk factors and D-dimer (Table 1
). Among controls, significant associations were
observed of baseline D-dimer values with circulating concentrations of
C-reactive protein and serum amyloid A protein but not with classic
risk factors or serum markers of inflammation or infection
(Table 2). In a comparison of men in the top third compared
with those in the bottom third of baseline D-dimer values (tertile
cutoffs, >94 versus <49 ng/mL), the odds ratio (OR) for CHD was 1.67
(95% CI, 1.31 to 2.13; 2-tailed
P<0.0001) after adjustments
for age and town
(Table 3). The OR increased slightly after further
adjustment for smoking, other vascular risk factors, and indicators of
socioeconomic status (OR, 1.79; 95% CI, 1.36 to 2.36). An
analysis restricted to the 407 cases and 1010 controls without
baseline evidence of CHD yielded an adjusted OR of 1.43 (95% CI, 1.04
to 1.98), which was not significantly different from the OR for all
cases and all controls
(
21=0.9;P>0.1).
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Meta-Analysis of Previous Prospective
Studies
Six previous prospective studies of D-dimer (including
4 studies in the general
population9 11 13 14
and 2 studies in cohorts defined on the basis of a history of
peripheral vascular
disease15 and myocardial
infarction16 ) were
identified. They involved a total of 905 CHD cases
(Figure 1) and had a mean weighted age at entry of 63 years
and a mean weighted follow-up of 5 years. All studies used
enzyme-linked immunoassays and adjusted for smoking, blood pressure,
and blood cholesterol; only 2 studies also adjusted for
plasma fibrinogen
concentration.9 13
Together with the present study, the 7 available prospective
studies included 1535 CHD cases, and there was no significant
heterogeneity among them
(26=11.1;
P=0.09). A combined
analysis yielded an OR of 1.7 (95% CI, 1.3 to 2.2:
Figure 2) in individuals with baseline D-dimer values in the
top third versus those in the bottom third, which corresponded to mean
usual log10 D-dimer values of 2.1 versus 1.7
ng/mL (corresponding to 126 and 50 ng/mL,
respectively).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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This prospective, community-based study is the first to demonstrate a clearly significant association between baseline concentrations of D-dimer antigen and CHD that seems largely independent of classic risk factors. These findings are reinforced by a meta-analysis of 6 smaller prospective studies. Collectively, these studies suggest that CHD risk is
70% greater in those in the
top third of D-dimer values compared with those in the bottom third
(Figure 2
).
Even so, the causal relevance of D-dimer to CHD remains
uncertain. The present study was unable to assess the effect of
adjusting for plasma fibrinogen concentration, but previous studies
have reported only modest correlations between D-dimer and plasma
fibrinogen values (for example,
r0.20)9 13 17
and little reduction in the strength of association between D-dimer and
CHD after correction for baseline plasma
fibrinogen.9 13 It
has also been suggested that D-dimer values may reflect inflammatory
states,2 and in the
present study there were significant associations of D-dimer values
with two circulating markers of inflammation but not with clinical
evidence of CHD at baseline. Conversely, the possibility that D-dimer
values predict prothrombotic states is suggested by preliminary
associations with venous thrombosis and other conditions (such as
atrial fibrillation) associated with intracardiac thrombosis and
embolism18 19 20
and the rapid normalization of D-dimer values after
cardioversion19 or
warfarinization20 in
patients with atrial fibrillation.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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Although there may be an association between circulating D-dimer values and CHD, further studies are needed to determine the extent to which this is causal.
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Acknowledgments |
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Professor A.G. Shaper established the British Regional Heart Study, which is a British Heart Foundation Research Group that also receives support from the Department of Health. K. Craig, F. Key, and L. Oxford provided D-dimer assays; Professor M.B. Pepys and J.R. Gallimore provided C-reactive protein and serum amyloid A assays; Drs H. Refsum and P. Ueland provided homocysteine assays; Dr M. Thomas, Dr Y.K. Wong, and Professor M. Ward provided C pneumoniae serology; Dr J. Atherton and Professor C. Hawkey provided H pylori serology; and Dr J. John provided valuable assistance. Dr Danesh was supported by a Merton College fellowship, the Frohlich Trust, and the Raymond and Beverly Sackler Award in the Medical Sciences. Drs Rumley and Lowe are supported by project and program grants from the British Heart Foundation.
Received January 24, 2001; revision received March 9, 2001; accepted March 15, 2001.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsReferences |
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J. D. Mills, M. W. Mansfield, and P. J. Grant Tissue Plasminogen Activator, Fibrin D-Dimer, and Insulin Resistance in the Relatives of Patients With Premature Coronary Artery Disease Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 704 - 709. [Abstract] [Full Text] [PDF]
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